Various opiate-derived antagonists such as naloxone, naltrexone, nalbuphone and nalbuphine are prepared by semi-synthesis from natural opiates such as morphine, thebaine or oripavine, Scheme 1. These compounds are used extensively in medicine as antagonists (naltrexone and naloxone) or mixed agonist/antagonist (nalbuphine). Naltrexone is used in the treatment of alcoholism and opioid dependence. Naloxone is the active ingredient in Narcan® for the reversal of opioid overdose and is also used in combination with buprenorphine (Suboxone®) for the treatment of opioid addiction. It is also employed with tilidine (Valoron N®) for the treatment of pain and with oxycodone (Targin®) for the prophylaxis and/or treatment of opioid-induced constipation. Nalbuphine is the active ingredient in Nubain®, which is used as an analgesic.

The synthesis of compounds such as naloxone, naltrexone and nalbuphone requires the oxidation of natural opiate alkaloids at the C-14 position. The synthesis of compounds such as naloxone, naltrexone, nalbuphone and nalbuphine requires the eventual replacement of an N-methyl group with, for example, an allyl, methylcyclopropyl, methylcyclobutyl, or other group. The synthesis of naloxone, naltrexone, nalbuphone and nalbuphine by several methods differing in concept as well as execution has been reported.
For example, naltrexone as well as R-methylnaltrexone, were prepared by N-demethylation of quaternary salts derived from oripavine followed by oxidation of N-methylcyclopropyl nororipavine.1 Similarly, nalbuphone and nalbuphine became available.2 N-Methylcyclopropyl nororipavine served as a convenient starting material for the improved synthesis of buprenorphine.3 Buprenorphine was also synthesized from oripavine by a newly discovered palladium-catalyzed N-demethylation/acylation protocol.4 In addition, it has been reported that the N-oxide of oxymorphone is easily demethylated with the Burgess reagent and that the intermediate iminium ion is trapped to form oxazolidines a and b in excellent yield and in a one-pot sequence from oxymorphone, as shown in Scheme 2.5

All of these efforts were the result of a focused program implemented to discover more efficient and environmentally friendly methods for the replacement of the N-methyl group in natural opiates with the appropriate alkyl group required for the medicinal agents.